This proposal outlines a 5-year training program for the successful transition of the investigator to an independent physician-scientist. The principal investigator completed Ph.D. and postdoctoral training in cancer biology and signal transduction, as well as structured clinical training in hematology, and plans to pursue an academic career investigating the pathogenesis of hematologic malignancies. The training plan proposed here will expand upon his clinical and scientific background and provide him access to a supportive environment that will prepare him for a career as an independent investigator. The research program described here focuses on the functional characterization of LNK mutations in myeloproliferative neoplasms (MPNs). The applicant will be mentored by Dr. Dan Link, a recognized leader in the investigation of normal and leukemic hematopoiesis. An advisory committee consisting of basic science and clinical/translational experts in hematology will provide additional scientific and career advice. Dysregulated JAK-STAT signaling is a hallmark of MPNs. Recent work has led to the identification of novel mutations in LNK, a negative regulator of JAK-STAT signaling, in MPNs. Therefore, the aims of this proposal are to determine the mechanisms by with LNK mutations modulate JAK-STAT signaling, and to characterize the ability of LNK mutations to contribute to MPN pathogenesis. To accomplish these goals, the investigator will evaluate JAK-STAT signaling in cell lines, murine bone marrow cells, and primary cells from MPN patients bearing LNK mutations. In addition, murine models will be developed, in order to determine how LNK mutations contribute to the development of myeloproliferatve disease in vivo. These studies will provide new mechanistic insights in the pathogenesis of MPNs, and potentially lead to the development of more effective treatment options for patients with MPNs. The applicant's laboratory is well equipped for these studies, and Washington University provides a rich environment for the training and development of the investigator. Access to core facilities and other scientific resources, as well as availability of clinical samples, is exceptional. Thus, the proposed studies and training environment will facilitate the candidate's long-term goal to become a successful independent investigator. PUBLIC HEALTH RELEVANCE: Myeloproliferative neoplasms (MPNs) are clonal hematologic malignancies that cause significant morbidity and have the propensity to transform to acute leukemia. Current treatment options for MPNs are limited. The studies proposed here will provide deeper insights in the pathogenesis of MPNs, and potentially lead to the development of more effective therapies for patients with MPNs.